Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation
of protein functions and assembly of macromolecular complexes. Despite these well-established
roles, such information has yet to be exploited for drug design. Here we show by nuclear
magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the
lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic
target--access alternative, minor population states in solution in addition to the
ligand conformation observed in crystal structures. These conformations collectively
delineate an inhibitor envelope that is invisible to crystallography, but is dynamically
accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor
envelope has led to the development of potent antibiotics with inhibition constants
in the single-digit picomolar range. The principle of the cryptic inhibitor envelope
approach may be broadly applicable to other lead optimization campaigns to yield improved
therapeutics.

Protein-protein interactions play a pivotal role in the regulation of various cellular
processes. The formation of higher order protein complexes is frequently accompanied
by extensive structural remodeling of the individual components, varying from domain
re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance
(NMR) spectroscopy is a powerful tool for macromolecular structure determination in
solution. It has the unique advantage of being capable of elucidati

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